Cognitive impairment is a distinctive component of the burden of disease in myotonic dystrophy (both DM1 and DM2). Although imaging and neuropsychological studies have profiled a spectrum of CNS issues in congenital, childhood, and adult onset DM1 and DM2, these features remain relatively uncharacterized. Knowledge of changes in brain circuitry that underlie the cognitive and behavioral phenotypes of DM is even more scant. A new study has utilized electrophysiological and optical imaging in order to better understand how brain circuitry is altered in DM.

Profiling Cerebral Cortical Circuitry in the DM2 Mouse Model

Dr. Timothy Ebner and colleagues at the University of Minnesota and University of Florida have evaluated the functional status of cerebral cortical circuitry in a mouse model of DM2 (Mbnl2 knockout). Their approach was to pair flavoprotein optical imaging with focal microelectrode stimulation/recording to determine changes in synaptic responses in control and DM2 mice. Since flavoprotein autofluorescence is neural activity-dependent and offers sufficient spatial/temporal resolution, it could be used as a tool to assess normal and abnormal responses to cortical stimulation.

Consequences of MBNL2 Depletion and Impact of MBNL1 Overexpression in DM2 Mice

Initial testing of the experimental paradigm in control mice showed both optical imaging and electrophysiological responses in ipsilateral and contralateral cortical areas; additional experiments confirmed that the contralateral response was mediated by the corpus callosum, a fiber tract known to be involved in DM patients. The spatial pattern of changes in flavoprotein fluorescence strongly correlated with neural activity measured by microelectrode and reported out on both excitatory and inhibitor activity.

Using these tools in DM2 mice, the duration of flavoprotein signal response to trains of microstimulation was increased in both ipsilateral and contralateral cortices in comparison to controls. This finding, coupled with observations that stimulation activated a larger area of cortex in DM2 mice versus controls, was consistent with increased cortical excitability resulting from MBNL2 depletion and its consequent changes in alternative splicing. Single pulse microstimulation yielded a center-surround inhibition response in controls that was absent in the DM2, further confirming the increased cortical excitability in this model. Some optical imaging and neurophysiological changes were reversed with human MBNL1 overexpression.

The publication of Ebner and colleagues validates a novel optical imaging approach to assessing changes in brain circuitry in DM models, reveals similar involvement of the corpus callosum in the mouse model and DM patients, and begins to resolve the synaptic changes and enhanced excitability that may underlie the white matter involvement and CNS phenotype in DM2. Taken together, findings show promise for efforts to understand CNS involvement in DM, but also highlight the challenges going forward to understand and treat this very important component of the burden of disease.

Reference:

Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy.
Chen G, Carter RE, Cleary JD, Reid TS, Ranum LP, Swanson MS, Ebner TJ.
Neurobiol Dis. 2018 Jan 10. pii: S0969-9961(18)30003-2. doi: 10.1016/j.nbd.2018.01.003. [Epub ahead of print]